PROJECT SUMMARY The overall goal of this K99/R00 proposal is to elucidate the extent to which small vessel cerebrovascular disease (svCBVD) and Alzheimer?s disease (AD) pathophysiology are additive or synergistic in their effects on neurodegeneration and cognition in midlife, and to determine if that differs across racial/ethnic groups. Comorbid svCBVD and AD pathology is observed in most dementia cases at autopsy, and is more prevalent in racial/ethnic minorities. Evidence is building that svCBVD has detrimental effects on amyloid clearance and tau phosphorylation, which exacerbates neurodegeneration and cognitive impairment in AD. It is crucial to include svCBVD, amyloid, and tau when considering primary drivers of disease, and neurodegeneration and cognition when considering the consequences of those primary drivers. While initial cognitive impairments in svCBVD are in executive function and those in AD are in memory, the consequences of the two become less distinct when they co-occur. Equally as important, studies in midlife are necessary to elucidate how svCBVD and AD pathophysiology initially develop, and how a particular mixture of AD and svCBVD influences disease progression. Aim 1 (K99) determines the biological consequence that svCBVD and amyloid have on tau- related neurodegeneration, and explores racial/ethnic differences in these associations. Aim 2 (K99) determines the cognitive consequence that svCBVD and amyloid have on tau-related memory dysfunction, and explores racial/ethnic differences in these associations. The central hypothesis is that, in middle age, individuals with svCBVD demonstrate more AD-related neurodegeneration and subsequently more cognitive impairment, and that this effect will be stronger in racial/ethnic minorities due to the higher prevalence of svCBVD. To achieve these goals, the applicant will undergo quick, but essential mentored training in three areas: (1) tau and small vessel cerebrovascular disease, (2) applied neuroscience, and (3) advanced statistical modeling. With these skills, the applicant will be well equipped to independently pursue Aim 3 (R00), which determines the longitudinal consequences that baseline svCBVD and amyloid have on neurodegeneration and memory decline over time. Understanding the consequences of single or mixed svCBVD and AD pathology will inform therapeutic targets and help determine whether interventional strategies need to differ by race/ethnicity. The strengths of this proposal include formal training in the underlying pathology represented by biomarkers and its connection to cognition, as well as formal training in statistics to rigorously implement a flexible National Institute on Aging(NIA)-Alzheimer?s Association-recommended research framework to directly address the current missions of the NIA. For the applicant, this accelerated training period will facilitate the development of an independent research program focused on large-scale neuroimaging studies of AD and related dementias in diverse populations.